Method of preparing dodecahydrophenanthrene compounds



- new nited S ates Patent 2,983,754 METHOD OF PREPARING DODECAHYDRO- PHENANTHRENE COMPOUNDS Norman L. Wendler, Summit, N.J., assignor to Merck & Co., Inc., Rahway, N .J., acorporation of New Jersey No Drawing. Filed Jan. 24, 1955, Ser. No. 483,819

10 Claims. 01. 260-5145) This invention relates to novel dodecahydrophenanthrene compounds and processes of preparing the same.

Patented May 9, 1961 Thedesired a,}9-unsaturated acids are produced by reacting the starting lactone with a strong, inorganic base such as alkali metal hydroxides or carbonates, alkaline earth metal hydroxides, alkali metal alkoxides, and the like. Generally, I prefer to effect the reaction in the presence of a suitable inert solvent for the lactone such as a lower aliphatic alcohol. veniently effected by heating a methanol solution of the Specifically, it is concerned with A -1-carboxyethy1- wherein n is 2 or 3, which are valuable products useful in the preparation of steroids such as aldosterone and the The reaction is most conlactone with an alkali metal hydroxide, for example, sodium or potassium hydroxide, or with an alkali metal alcoholate, for example sodium methylate or potassium ethylate. After the reaction is complete, the desired c p-unsaturated acid can be readily recovered by acidifying the reaction mixture, concentrating the resulting solution to dryness, dissolving the residue in ethyl ether,

and concentrating the resulting solution.

The process of the present invention is particularly useful in preparing A -1-carboxyethyl-ZAbB-dimethyl-4- keto 7a hydroxy 4aa,8a,B,10aB dodecahydrophenanthrene and 13 -1-carboxypropyl-2,4bfl-dimethyl-4 keto-7mhydroxy-4aa,8a}3,l0a;8-dodecahydrophenanthrene, which,

as will be pointed out in detail hereinafter, are very useful in the preparation of valuable steroid compounds. These products are produced by the hydrolysis of 3ahydroxy 11 keto etiochololactone or acyl derivatives 0 thereof, and 3u-hydroxy-11 keto-D-homoetiochololactone like, can be prepared by reacting compounds having the structural formula o it t OH -(cm)n wherein n is the same as above, and R is hydrogen or L l acyl with a base.

It is an object of the present invention -to provide a process for the preparation of novel A -l-carboxyethyl or carboxyp-ropyl dodecahydrophenanthrene compounds.

Another object is to provide A -1-carboxyethyl-2Abfiwherein nis 2 or 3 wit-ha base. The lactone employed as the starting material in my process can be saturated or unsaturated and can contain other substituents such as al-kyl; hydroxy; keto, acyloxy, and the like.

or its acyl derivatives respectively.

The novel dodecahydrophenanthrene compounds of the present invention can be readily converted into useful derivatives thereof such as esters in accordance with methods known in the art. Thus, these compounds can be acylated to form the corresponding 3-acyloxy cornpounds. For example, the dodecahydrophenanthrene compounds can be reacted with acetic anhydride in the presence of pyridine to form the corresponding 3-acetoxy compounds, or with benzoyl chloride to produce the corresponding 3-benzoxy derivative. Also, the dodecahydrophenanthrene compounds, or the 3-acyloxy derivatives thereof, can be readily esterified, for example, by reaction with an alcohol in the presence of a small amount of an acid, to obtain the corresponding dodecahyd-rophcnanthrene compound having an esterified carboxylic acid group.

In accordance with another embodiment of my invention, it is now found that A -I-carboXyethyI-ZAbB- dimethyl 4 keto 7oz hydroxy -4ae,8a;3,l0a/3-dodecahydrophenanthrene can be prepared from 3a-hydroxy 11,17-diketoetiocholane by the process which can be shown as follows:

0 CH3 ll 0 CH CH In this process the starting material, 3a-hydroxy- 11,17-diketo-etiocholane (XI) is reacted with an organic per acid to produce 3u-hydroxy-1l keto-etiochololactone (XII) which on treatment with a base is converted to the desired dodeca-hydrophenanthrene compound.

Alternatively, in the above process, the intermediate etiochololactone (XII) can be acylated to produce the 3-acyloxy derivative which can then be converted to the dodecahydrophenanthrene compound by reaction with a base.

Pursuant to a further embodiment orf my invention, I

have found that A -l-carboxypropyl-2,4-bfl dimethyl-4 keto 4 7a =hydroxy 4aa,8a;3,l0a;8 dodecahydrophenanthrene can be prepared from 3a-acetoxy-1L17-diketoetiocholane by the process which can be shown as follows:

CH3 CH;

H ti 1 t CH3 OH RO-- HO I II CH: CH:

CH: O--CCH8 0R "-CHg-NH en OH CH IV III 0H CH t v R 0-- Ito-- v a v1 CH acmnooon HO- 3 VII wherein R represents an acyl group.

In accordance with the foregoing flowsheet Swacyloxy- 11,17-diketo-etiocholane (I) is converted to the cyanohydrin, of 3a-l7fldihydroxy-l1-keto-17-isoetianic acid (II); acylation of this compound by reaction with an acylating agent teams the corresponding diacyl derivative (III); reduction of the diacyl derivative by reaction with aluminum hydride and reaction with acetone yields the oxazoli'dine derivative ocE 3a,11 9,17B-trihydroxy-ZO-aminomorpregnane (IV); diazotization ofv this byreact-ion so ium nitrite in aqueous. ace ic onion on on 0 one vrn IX f CH; on, nc=non ---0rr -on on 0H r 1 HO--- no-- on; on;

0 0 0 OH -(cHmc00 wherein R represents an acyl group.

In this series of reactions, the starting material, 3a, 1700 dihydroxy 11,20 'diketo 21 acyloxy p regnane (VIII) is reduced by reaction with lithium aluminum hydride to form the pentol (IX); treatment of this compound with periodic acid followed by treatment of the resulting reaction product yields the oxime (X); and redu t n o the o tne it o n in t e p e en e of a noble met l catalyst a ords 3, 13,1 r ys1r xy+ 'am nQ rpreg a-n d e ot ze of this by r action thrwdiumr uiite in gu sasetic acid acylation of the resulting product followed by oxidation with chromic acid gives 3aaacyloxy-l 1,17a-diketo-D- homoetiocholane (V). This compound is then converted to A 3- 1 carboxypropyl 2,4b5 dimethyl 4 keto- 7 hydroxy 4aa,8afl,10a5 dodecahydrophenanthrene as described above.

In the above-described methods for the preparation of A 1 carboxypropyl 2 4b/3 dimethyl 4 keto- 7a hydroxy 4au,8a,8,10a 3 dodecahydrophenanthrene, although any acyl group can be utilized for the purpose of protecting the hydroxy substituents, I have found it to be particularly advantageous to employ lower fatty acid acylating agents for this purpose. Generally, I prefer to use an acetyl group for the protection of the hydroxy substituents, since these derivatives are most conveniently prepared.

The novel dodecalhydrophenanthrene compounds =obtamed in accordance with the present invention are useful as intermediates in the preparation of valuable steroid compounds. Thus, A 1- carboxyethyl 2,4bB dimethyl 4 keto 7oz hydroxy 4au,8a,8,10afi dodecahydrophenanthrene can be converted to the valuable mineral factor of the adrenal cortex as follows:

The A -1-carboxyethyl-2,4bfl-dimethyl-4-keto-7a hy droxy 4au,8afl,10afi-dodecahydrophenanthrene is acetylated by reaction withacetic anhydride to form the 70:- acetoxy derivative; this derivative is then esterified by reaction with methanol in the presence of HCl to form the corresponding methyl ester; reaction of this methyl ester w1th N-bromosuccinimide followed by treatment of the react on product with potassium acetate in acetone and hydrolysis of the resulting reaction product yields A 70:- hydroxy-4-keto-2-(hydroxymethyl) 4bfi-methyl-4a 8afi, l'pafl-dodecahydrophenanthryl-lfl-propionic acid; oxidatron of this product with manganese dioxide and treatment of the oxidized product with methanol in the presence of acid produces A -7a-hydroxy-4-keto-2-(dimethoxy methyl)-4b;5', methyl 48oz; 8afi,10a 8-dodecahydrophenanthryl-lfi-propionic acid; acetylation of this product with acetic anhydride and treatment of the acetylated product with thionyl chloride afiords A -7a-acetoxy-4-keto-Z(dimethoxymethyl) 4hr? methyl 4aa,8aB,10aB-dodecahydrophenanthryl-l/i-propionic acid chloride; reaction of this compound with diazomethane produces A -7a-acetoxy-4-keto-2 (dimethoxymethyl) 4hr? methyl-4aa,8a,B, 10afl-dodecahydrophenanthryl ,6 propiodiazomethyl ketone; treatment of this compound with acetic acid yields 3a, l7a-dihydroxy-11, l7-diketo-18, l8-dimethoxy-D-homoenocholane; oxidation of this compound with sodium meta-periodate followed by air oxidation and acetylation of the oxidized product with acetic anhydride in the pres ence of pyridine affords 3a-acetoxy-18,18-dimcthoxy-l1- ketoetiobilianic acid; esterification of the latterproduct with methanol in the presence of a small amount of acid and treatment of the esterified product with sodium ethylate results in obtaining 3a-hydroxy-l1,17-diketo-l8,18-dimethoxy-etiocholane; reaction of this product with potassiumxacetylide inliquid ammonia followed by catalytic reduction .afiords 3 u,17-dihydr0xy-11-keto-18,18-dimethoxy-l7-viny1-etiocholane; bromination of this product with: phosphorous tribromide followed by treatment of the brominated product with potassium acetate produces A r3a-hydroxy-l1-keto-18,18 dimethoxy 21 acetoxypregnene; reaction of this product with osmium tetroxide and treatment of the resulting osmate ester with acetic anhydride yields 3a,20,21-t1iacetoxy-11-keto-17a-hydroxy- 18,18-dimethoxy-pregnane; reaction of this product with zinc in toluene. and hydrolysis of the resulting product with an alkali afiords 3u,21-dihydroxy-11,20-diketo-18, IS-dimethoxy-piegnane; treatment of this compound with N-bromoacetamide followed by acetylation of the resultingreaction product with acetic anhydride in the presence of pyridine, reaction of the acetylated product with bromine, and the treatment of the resulting hrorninated product with semiearbazide aifords. 13,18

0 dimethoxy-21-acetoxy-pregnane-3,20. bissemicarbazone, reduction of this product with sodium borohydride, and hydrolysis of this reduced product with pyruvic acid affords aldosterone ZI-monoacetate.

The A 1 carboxypropyl-2,4b-dimethyl-4-keto-7a-hydroxy 430:,83BJ0313 dodecahydrophenanthrene can be converted to the corresponding l-carboxyethyl compound by the Barbier-Wieland method, and the product so obtained can be converted to aldosterone 21-monoacetate by the procedures described above.

The following examples are presented to illustrate the methods of preparing the new compounds of the present invention.

EXAMPLE 1 Preparation of A -1-carboxyethyl-Z,4b-dimet'hyl-4-ket0-7ahydroxy 4aa,8a;3,10afl-dodecahydrophenanthrene from 3a-hydroxy-Z 1 -keto-etioch0l0lact0ne To 0.5 g. of 3o -hydroxyall-keto etiocholactone in 10 ml. of refluxing methanol was added over the course of one hour 5.2 ml. of 0.27 N methano lic sodium methoxide. Removal of the methanol in vacuo and addition of ether afforded the sodium salt of A -l-carboxyethyl-2,4b-dimethyl 4 keto-7a-hydroxy-4aa,8a/3,IOafi-dodecahydrophenanthrene which was filtered, washed with ether and dissolved in a few m1 of water. Addition of dilute hydrochloric acid followed by ether extraction in the usual way gave the crystalline unsaturated acid which was recrystallized from acetone petroleum ether; glistening plates 350 mg, M.P. 178-9 50 mg., M.P. 174-6"; corrected yield, 89%. Further recrystallization did not raise the M.P. above l78-9; [a] 32.4 (C=0.79)

ZEQ 237 u, =12,1e0; x313}? 3-4, 5.87, 6.00, 6.12,.

Analysis. Calc d. for C H O C, 71.23; H, 8.81. Found: C, 70.57; H, 8.79.

Preparation of Sa-hydroxy-JI-keto-etiochololactone The starting material used in the foregoing example can be prepared from 3u-acetoxy-11,20-diketo-17u-hydroxyepregnane as follows: i

.To a solutionof 3u-acetoxy-11,20-diketo-17a-hydroxy pregnane, M.P. 202-5 C. (60 g.) in acetic acid (600 ml.) was added chromic oxide (11.3 g.; equivalent ratio 1.1:1) in water (5 ml.) and acetic acid ml.). After three days. at 25 C. the solvent was removed in vacuo, water added'and the product extracted with ethyl acetate. The organic solution was washed with 5% aqueousso' dium carbonate and Water and dried over anhydrous magnesium sulfate. The residue remaining after removal ofthe solvent was dissolved in 2:1 petroleum ether-ben- Zone (1200 ml.) and chromatographed on acid-washed alumina (500 g.). The column was eluted with petroleum ether-benzene, benzene and benzene-chloroform mixtures. Ifrom the petroleum ether-benzene fractions there was obtained 3uacetoxy-11,17-diketo etiocholane; 21.5 g., M.P. l59-161 C. and 6.5 g., M.P. 156-9 C.

3oc-8C6tOXY-1Ll7-dik6to etiocholane (14.0 g.) was dissolved in a solution of sodium hydroxide (12.0 g.) in 50% methanol (240 ml.). After 30 minutes at 25 C. acetic acid (18ml) was added, the mixture was concentrated to ml. and Water (300 ml.) was added. The precipitated 3a-hydroxy 11,17 diketo-etiocholane was filtered, washed several times with water and dried in vacuo; 12.2 g., M.P. 1868 C. 1

To a solution of 3a-hydroxy-11,17-diket-o-etiocholan (I) (15.0 g.) in benzene (225 ml.) was added perbenzoic acid in benzene (100 ml., 0.32 M). After 48 hours at room temperature the mixture was concentrated in vacuo to a thick slurry, triturated with ether (75 1111.); filtered and washed With ether. Crystallization from acetone-ether gave 30: hydroxy 11-ketoetiochololactone as massive prisms 7.3 g., M.P. 212-8 C., 3.4 g. M.P.

202-6 C. (75%). Recrystallization from acetonepetroleum ether raised the melting point to 216-220 C.; [ab-12 (C=1.08);

iggf 2.92, 5.80, 5.85,

Analysis.Calcd. for C H C, 71.23; H, 8.81. Found: C, 71.65; H, 9.05.

EXAMPLE 2 Preparation of A -J-carboxyethyl-2,4b-dimethyl-4-keto 7ahydroxy 4aa,8a,8,10afiedodecahy'drophenanflzrene from 3ot-acetoxy-11-ket0-etiochol0lactone To a stirred refluxing solution of 3a-acetoxy-11-ketoetiochololactone (100 mg.) in 15 ml. of water was added dropwise over one hour a solution of 5.7 ml. of 0.101 N sodium hydroxide mixed with 10 ml. of methanol. The resulting reaction mixture was concentrated under diminished pressure, diluted with water and traces of neutral material extracted with ether. Acidification of the solution followed by ether extraction and evaporation of the ether extracts aiforded crystalline A -1-carboxyethyl-2,4b-dimethyl 4 keto 7m-hydroxy 4am,8afl,- IOaB-dodecahydrophenanthrene melting at 176178 C.

Preparation of 3a-acet0xy-11-keto-etioch0l0lactone The starting material used in the foregoing example is prepared from 3a-acetoxy-11,17-diketo-etiocholane as follows:

To a solution of Sa-acetoxy-l1,17-diketo-etiocholane (1.73 g.) in 5 ml. of acetic acid was added a solution of peracetic acid in acetic acid (4.8 ml., 1.25 M), and the colorless mixture was kept at 25 C. for 24 hours. Slow addition of 100 ml. of cold water precipitated 3a-acetoxyll-keto-etiochololactone in the form of elongated prisms melting at 181-184 C.; [eth l-14 1(C=0.77);

xggf 5.78, 5.86,.

Analysis.-calcd. for C H O C, 69.58; H, 8.34. Found: C, 69.24; H, 8.10.

EXAMPLE 3 Preparation of A -I-carboxypr0pyl-2,4b-dimethyl-4-ket0- 7a-.hydr0xy 4au,8a;3,10a 8 dodecahydrophenanthrene from 3a-acet0xy-11 -ket0-D-h'omoetiochololactone A solution of 3a-acetoxy-11-keto-D-homoetiochololaotone (188 mg.) in methanol (20 ml.) and aqueous 1.00 N sodium hydroxide (1.50 ml.) was refluxed one hour under nitrogen. Acetic acid (0.5 ml.) Was added, the solvent removed in vacuo and the acidic product extracted into ether and worked up in the usual way. It crystallized spontaneously on removal of solvent and was recryse tallized several times from acetone-ether; matted needles, M.P. 164-6 C.; [a] 27 (C=0.78);

237.5 mp, e 12,500; xgfif 3-4, 5.85, 6.00, 0.18,.

Analysis.-Calcd. for C H 0 C, 71.81; H, 9.04. Found: C, 71.70; H, 8.79.

EXAMPLE 4 Preparation of 3a-acet0xy-11-keto-D homoetiochololactone from 3a,] 7a,dihydroxy-11,20-diketo 21 acetoxy pregnane 8 reaction mixture was filtered and the filtrate evaporated to give 6 g. of 3a,l1,17u,20,21-pentahydroxy pregnane.

The crude pentol (6 g.) in 250 ml. of dioxane was treated with 3.72 g. of periodic acid (H 10 in '70 ml. of water and the reaction solution allowed to stand for 4 hours. At the end of this period the reaction mixture was evaporated to near-dryness, the residue extracted with ether and the ether extract washed with water and evaporated to an oil. This oil Was dissolved in ml. of methanol and treated with 2.5 g. of hydroxylamine hydrochloride and 3 g. of sodium acetate in 10 ml. of water, heated to boiling on a water bath and allowed to stand overnight at room temperature. The reaction mixture from the oximation was evaporated nearly 'to dryness, the residue dissolved in ether and the oxime 3 0:,17ot-dihYdIOXY-1 1-keto-20-oximino-2l-nor-pregnane extracted with 10% aqueous sodium hydroxide. Acidification of the alkaline extracts with hydrochloric acid deposited the crude oxime as a gum. The latter was taken up in ether-ethyl acetate, dried over magnesium sulfate and evaporated to give 3.8 g. of the oxime as an amorphous residue.

A solution of 2.8 g. of the above oxime in 50 cc. of acetic acid was hydrogenated at atmospheric pressure and room temperature using 280 mg. of platinum oxide. The uptake of hydrogen was rapid and conformed to essentially 1 mole. The catalyst was filtered off and the filtrate containing the 3a,17a-dihydroxy-1l-keto-ZO-amino- 21-norpregnane made ca. 50% with water, then treated dropwise at 0 C. with a solution of 1 g. of sodium nitrite in 30 ml. of water. The reaction product, which had largely separated (1.6 g.) during the overnight reaction period, was acetylated with acetic anhydride and pyridine followed by chromic acid oxidation and chromatographed over acid washed alumina. Fromthe l-2% ether in benzene eluates was obtained 340 mg. of 3a acetoxy 11,170: diketo D-homoetiocholane, M.P. 1645-1655 C. The 10% ether-benzene eluates yielded 50 mg. of Sa-acetoxy-l1,l7-diketo-D homoetiocholane, M.P. 203-6 C.

3a. acetoxy 11,17 diketo-D-homoetiocholane (1.08 g.) in benzene (14 ml.) was mixed with perbenzoic acid in benzene (19.2 ml., 0.391 M). After 3 days at 25 the remaining per acid was destroyed and the reaction mixture worked up by addition of water and ether extraction. The product 3a-acetoxy-11-keto-D- homoetiochololactone was crystallized from ether; 760 mg., M.P. 170-2 C.; 102 mg., M.P. l63.6 C. Recrystallization from ether-petroleum ether gave plates M.P. 172-4 C.; [ab-24 (C=O.77);

Aanalysis.Calcd. for C I-1 0 C, 70.18; H, 8:57. Found: C, 69.78; H, 8.31.

EXAMPLE 5 Preparation of 3a-acetoxy-11-keto-D-hom0etiochololactone from 3a-acetoxy-11,17-diketoeti0ch0lane 3a-acetoxy-11,17-diketoetiocholane (5 g.) in cc. of ethanol was cooled to 0 and treated with 30 g. of potassium cyanide, followed by dropwise addition of 34 ml. of glacial acetic acid at such a rate that the temper ature did not exceed 5-8 C. After the completion of addition of acetic acid the reaction mixture was allowed to stir at 0 C. for one hour and at room temperature for two hours. At the end of this digestion period the reaction mixture was added to 5 volumes of water and the precipitated oily product extracted with ethyl acetate. The ethyl acetate extract was washed with water, dried over magnesium sulfate and concentrated in vacuo to an oil. The oily 3u,17-dihydroxy-1l-keto-l7-cyanoetiocholane was acetylated at room temperature for 15 hours with 25 cc. of pyridine and 10 cc. of acetic anhydride, he a tylation reaction p oduct was. eated with excess a we to ice-water and the product extracted with ethyl acetate. The ethyl acetate solution waswashed with dilute aqueous HCl and NaHCO solution, dried over magnesium sulfate, concentrated and'crystallized from ethyl acetatepetroleum ether to produce 3u,17;3-diacetoxy-1l-keto- 17a-cyano-etiocholane M.P. 183-5 C.

A solution of twolgrams" of this cyanohydrin acetate was dissolved in50'cc. ofbenzene and treated with 2 g. of lithium aluminum hydride in 250 cc. of ether. The reaction mixture was refluxed for 1 hour and then the excess lithium aluminum hydride cautiously decomposed with water. The solid was filtered, dried in a vacuum desiccator and then extracted with acetone in a Soxhlet extractor for 5-6 hours. Evaporation of the acetone left an oil. The latter was taken up in ether and extracted with dilute HCl. Neutralization of the HCl extract deposited the oxazolidine derivative of 304,115,- 17 ,8 trihydroxy 20-amino-21-norpregnane which was crystallized from ethyl acetate petroleum ether, melting at l90--l92 C.

Analysis.Calcd. for C H O N: C, 73.20; H, 10.32; N. 3.72. Found: C. 73.45; H, 10.29; H, 3.73.

A solution of 1 g. of the above amine in 95 ml. of 5% aqueous acetic acid was chilled to C. and treated with a solution of 0.35 g. of sodium nitrite in 8 cc. of water. The reaction mixture was allowed to stand 3 hours at 0 C. and overnight at room temperature. During this period 0.6-0.7 g. of solid product separated. The latter was acetylated with 4 ml. of pyridine and 2 ml. of acetic anhydride at room temperature overnight followed by oxidation in 5 ml. of acetic acid containing 130 mg. of chromic acid. Chromatography of the product on acid-washed alumina yielded from eluates of 1-5% ether in benzene, 340 mg. of 3a-acetoxy-1l,l7a-diketo- D-homoetiocholane as needles from acetone-petroleum ether, M.P. 167-8 C.; x] +28.7 (C=1.02).

Analysis.--Calcd. for C H O C, 73.33; H, 8.88. Found: C, 73.50; H, 8.77.

2,4-dinitrophenylhydrazone crystallized as yellow needles from methanol-ethyl acetate, M.P. 220-225 C.

Analysis.--Calcd. for C H O N N, 10.37. Found: N, 10.48.

The eluates from the chromatography consisting of l020% ether in benzene yielded 52 mg. of 3a-acetoxy- 1l,l7-diketo-D-homoetiocholane as plates from acetoneether, M.P. 205-7 C.; [a] +23.0 (C=1.09).

Analysis.Calcd. for C H O C, 73.33; H, 8.88. Found: C, 73.29; H, 8.91.

2,4-dinitrophenylhydrazone crystallized as needles from methanol-ethyl acetate, M.P. 281-3".

Analysis.Calcd. for C H O N N, 10.37. Found: N, 10.54.

The 3a-acetoxy-11,17u-diketo-D-homoetiocholane was then treated following the method described in Example 4 to obtain 3u-acetoxy-l1,17a-diketo-D-homoetiochololactone.

Various changes and modifications of the invention can be made and, to the extent that such variations incorporate the spirit of this invention, they are intended to be included within the scope of the appended claims.

I claim:

1. The process which comprises reacting a compound having the structural formula gen and lower fatty acid radicals, with a base to produce a compound having the structure wherein n is the same as defined above.

2. The process which comprises reacting 3u-hydroxyll-keto-etiochololactone with an inorganic base to produce A 1 carboxy-ethyl-2,4bB-dimethyl-4-ketoJot-hydroxy-4au, 8afi, 10afl-do decahydropheuanthre ne.

3. The process which comprises reacting 3u-acyloxyll-keto-etiochololactone wherein the acyl group is a lower fatty acid radical with an inorganic base to produce A -1- carboxyethyl 2,4bfi dimethyl 4 keto 7a hydroxy- 4aa,8a,3,10afi-dodecahydrophenanthrene.

4. The process which comprises reacting 3u-hydroxy- 11-keto-D-homoetiochololactone with an inorganic base to produce A -l-carboxypropyl-Z,4b 3-dimethyl-4-keto-7ahydroxy-4aa,8a,8,lOafi-dodecahydrophenanthrene.

5. The process which comprises reacting 3u-acyloxy- 11-keto-D-homoetiochololactone wherein the acyl group is a lower fatty acid radical with an inorganic base to produce A -1-carboxypropyl-Z,4b 8-dimethyl-4-keto-7a-hydroxy-4aa,8afi,I'Oafi-dodecahydrophenanthrene.

6. The process which comprises reacting 3u-hydroxy- 11,17-diketo-etiocholane with an organic per acid to produce 3ot-hydroxy-ll-keto-etiochololactone, and treating said lactone with a base to obtain n -l-carboxyethyl- 2,4bf3 dimethyl 4 keto 7oz hydroxy 4aa,8a}9,10a 3- dodecahydrophenanthrene.

7. The process which comprises reacting 3u-hydroxy- 11,17-diketo-etiocholane with perbenzoic acid in benzene to produce 3u-hydroxy-1l-keto-etiochololactone, and heating said lactone with sodium methoxide in methanol to obtain A -1-carboxyethyl-2,4bfi-dimethyl-4-keto-7a-hydroxy-4aa, 8 a8, 10a 3-dodecahydrophenanthrene.

8. The process which comprises reacting 3oc-3CYIOXY- 11,17-diketo-etiocholane with hydrogen cyanide to form 301,17fl-dihYdI'OXY-l l-keto-17m-cyano-etiocholane; acylating the latter product to form the corresponding 3,17-diacyloxy derivative, reducing this diacyloxy compound with lithium aluminum hydride and treating the reduced product with acetone to form the oxazolidine derivative of 3a,11p,17B-trihydroxy-20-amino-2l-norpregnane, diazotizing said oxazolidine derivative, acylating the diazotized product, oxidizing said acylated product to produce 3ozv acyloxy-l1,17a-diketo-D-hornoetiocholane, oxidizing this product with an organic per acid to obtain 3m-acyloxy- 11-keto-D-homoetiochololactone, and treating this lactone with a base to produce A -1-carboxypropyl-2,4b 3-dimethyl 4 keto c hydroxy 4aa,8afi,10afl dodecahydrophenanthrene.

9. The process which comprises reacting 3m-acetoxy- 11,17-diketo-etiocholane with potassium cyanide in the presence of acetic acid to form 30:,17f3-dihYdI'OXY-11-k6t0- 17or-cyanoetiooholane, treating this product with acetic anhydride in the presence of pyridine to obtain the corresponding 3,17-diacyloxy derivative, reducing this diacyloxy compound with lithium aluminum hydride and treating the reduced product with acetone to produce the oxazolidine derivative of 3u,11fi,17p-trihydroxy-20- amino-Zl-norpregnane, reacting said oxazolidine derivative with sodium nitrite in the presence of acetic acid, acylating the resulting product with acetic anhydride in the presence of pyridine, reacting the resulting product with chromic acid in acetic acid to produce 3u-acetoxy- 11,l7oL-dlkCiO-D-h0ll106il0611018116, oxidizing this product by reaction with perbenzoic acid to obtain 3u-acetoxy- 1l-keto-D-homoetiochololactone, and heating this prod- T1 not with sodium hydroxide in methanol to produce A l! carboxypropyl 2,4bfl dimethyl 4 keto 7a hydroxy- 4aa,8a5,10a/B-dodecahydrophenanthrene.

10. The process which comprises reacting 3a,17adihydroxy-l 1,20-d1'keto-21-acetoxy pregnane with lithium aluminum hydride to produce 3a,11,17ot,20,21-pent-ahydroXy pregnane, reacting this product with periodic acid, treating the resulting product with hydroxylamine to produce 304,170: dihydroxy-l l-keto-ZO-oxirnino-Zl-norpregnane, reducing this product in acetic acid with hydrogen in the presence of platinum catalyst to obtain 300,17- di'hydroxy-11-keto-20-arnino-2l-norpregnane, reacting this product with sodium nitrite, treating the resulting reaction product with acetic anhydride in the presence of pyridine followed by chromic acid-acetic acid oxidation to obtain 3a acetoxy-l1,17aediketo-D-homoetiocholane, oxidizing this product by reaction with perbenzoic acid to obtain 3a-acetoxy-11-keto-D-homoetiochololactone, and heating this product with sodium hydroxide in methanol to produce A 1 carboxypropyl-Z,4bB-dimethyl-4-keto-7a-hydroxy-4au,8a,8,10afl-dodecahydrophenanthrene.

References Cited in the file of this patent UNITED STATES PATENTS 2,889,355 Ruzicka et 'al June 2, 1959 

1. THE PROCESS WHICH COMPRISES REACTING A COMPOUND HAVING THE STRUCTURAL FORMULA 